Complex neoplasms that can produce symptoms throughout the body

"These are unique tumors, quite different from prostate or breast cancer, because these tumors may also secrete hormones that cause patients to feel ill. And that's unusual for most common cancers." –Dr Larry Kvols

Symptoms of NETs

Many neuroendocrine neoplasms are clinically silent (asymptomatic) or only produce symptoms caused by mass (eg, pain, obstruction, bleeding). However, grade 1 and grade 2 NETs are more prone to secrete hormones than are higher grade neuroendocrine carcinomas,1-3 which can cause some of the associated symptoms and syndromes (see table).4These symptoms are often nonspecific and can be easily mistaken for those of other conditions.1 They include flushing, fatigue, diarrhea, hypoglycemia, skin changes, abdominal pain/discomfort, and wheezing.1-3 NETs usually metastasize to the liver and/or bone before patients experience symptoms.4

NETs associated with the secretion of hormones or peptides are known as functional NETs.5 Identifying and testing for these hormonal syndromes may be useful in diagnosing functional NETs.

Clinical syndromes and their incidence*

*Does not include carcinoid syndrome. See below for a detailed discussion of carcinoid syndrome.

Carcinoid syndrome

The hormones and peptides secreted by NETs may cause carcinoid syndrome.11Carcinoid syndrome is the primary clinical manifestation of NETs, occurring in 8% to 35% of patients.12

Other clinical syndromes: a closer look

In addition to carcinoid-syndrome–producing neoplasms, functional NETs, notably pancreatic NETs, can be characterized by their potential to secrete hormones or peptides, such as insulin, gastrin, glucagon, vasoactive intestinal polypeptide (VIP), and somatostatin, causing characteristic hormonal syndromes.13 Some of these are discussed here.

The diagnosis of insulinoma requires demonstration of hypoglycemia in the presence of inappropriate hyperinsulinemia.18

Gastrinomas: Gastrinomas can occur as isolated, sporadic tumors or as multiple, MEN-1–associated tumors19 and usually are located in the pancreas or the duodenum.20 Patients typically present with abdominal pain related to peptic ulcer disease (PUD), diarrhea, and gastroesophageal reflux disease (GERD).19,21 Gastrinomas cause a clinical syndrome known as Zollinger-Ellison syndrome (ZES).21,22 ZES should be suspected if PUD is recurrent, resistant to therapy, severe, or familial; PUD is associated with complications, endocrinopathies, prominent gastric folds, or hypergastrinemia; or Helicobacter pylori and nonsteroidal anti-inflammatory drug (NSAID) use are absent.1,19

A diagnosis of ZES should be considered if there is evidence of inappropriate hypergastrinemia (ie, in the presence of acidic pH).19,21

Glucagonomas: Glucagonomas secrete excessive amounts of glucagon, causing glucose intolerance, weight loss, and a pathognomonic rash known as necrolytic migratory erythema (see figure). This rash is characterized by raised erythematous patches that begin in areas of friction, such as the perineum, and eventually can involve the trunk and extremities. Although necrolytic migratory erythema is found in up to 90% of patients with glucagonomas, it also can occur in cirrhosis, pancreatitis, and celiac disease. Thus, diagnosis of a glucagonoma depends on the demonstration of pathologic hyperglucagonemia.14,19

VIPomas: VIPomas cause a distinct clinical syndrome known by several names, including Verner-Morrison syndrome, pancreatic cholera, and WDHA (for watery diarrhea, hypokalemia, and achlorhydria).14,22 Patients typically present with severe, large-volume, watery diarrhea, hypokalemia, and hypochlorhydria. The definitive diagnosis requires demonstration of elevated serum concentrations of VIP and localization of a pancreatic NET in the presence of large-volume secretory diarrhea.14,22

Somatostatinomas: Somatostatinomas cause a clinical syndrome characterized by diabetes mellitus, cholelithiases, diarrhea, and steatorrhea.14,22Diagnosis is based on the demonstration of hypersomatostatinemia in the presence of a pancreatic or duodenal mass and at least some features of the clinical syndrome.14,22